Processes for the manufacture of a pharmaceutically active agent

ABSTRACT

Disclosed herein are processes for the preparation of a pharmaceutically active agent and pharmaceutically acceptable salts thereof.

FIELD OF THE INVENTION

The present invention relates to the preparation ofN-(2-(6-fluoro-1H-indol-3-yl)ethyl-(2,2,3,3-tetrafluoropropoxy)benzylamineand pharmaceutically acceptable salts thereof.

BACKGROUND ART

The 5-HT₆ receptor is a member of the G-protein coupled receptorsuperfamily of serotonin receptors, and, like the 5-HT₄ and 5-HT₇receptors, is positively coupled to adenylate cyclase (Monsma, F. et al.Mol. Pharmacol. 1993, 43, 3, 320-327). The rat 5-HT₆ receptor was firstcloned in 1993 and the cloning of the human homologue, to which itshares an 89% sequence identity, was reported in 1996 (Kohen, R. et al.J Neurochem. 1996, 66, 1, 47-56). The localization of 5-HT₆ receptors inrat brain has been studied using mRNA quantification by Northernanalysis and RT-PCR, immunohistochemistry, and autoradiography (Ward,R., et al. J. Comp Neurol. 1996, 370, 3, 405-414; and Ward, R. et al.Neuroscience 1995, 64, 4, 1105-1111). These methods have consistentlyfound high levels of the receptor in olfactory tubercle, hippocampus,striatum, nucleus accumbens, and cortical regions. 5-HT_(S), receptorsare either absent or present in very low levels in peripheral tissues.

Much of the early interest in the 5-HT₆ receptor was due to theobservation that several psychotropic agents are high affinityantagonists at the human 5-HT₆ receptor. These compounds includeamitriptyline (Ki=65 nM) and the atypical antipsychotics clozapine(Ki=9.5 nM), olanzapine (Ki=10 nM), and quetiapine (33 nM). See Roth, B.L., et al. Pharmacol. Exp. Ther. 1994, 268, 3, 1403-1410.

The use of selective 5-HT₆ receptor antagonists to treat cognitivedysfunction is widely accepted and is based on several lines ofreasoning. For example, selective 5-HT₆ receptor antagonists modulatecholinergic and glutamatergic neuronal function. Cholinergic andglutamatergic neuronal systems play important roles in cognitivefunction. Cholinergic neuronal pathways are known to be important tomemory formation and consolidation. Centrally acting anticholinergicagents impair cognitive function in animal and clinical studies and lossof cholinergic neurons is one of the hallmarks of Alzheimer's disease.Conversely, stimulation of cholinergic function has been known toimprove cognitive performance and two agents currently approved for thetreatment of cognitive deficit in Alzheimer's disease, galantamine anddonepezil, are both acetylcholinesterase inhibitors. The glutamatergicsystem in the prefrontal cortex is also known to be involved incognitive function (Dudkin, K. N., et al. Neurosci. Behav. Physiol.1996, 26, 6, 545-551).

The activity of selective 5-HT₆ receptor antagonists is alsodemonstrated in animal models of cognitive function. Since thedisclosure of the first selective 5-HT₆ receptor antagonists, there havebeen several reports on the activity of these selective compounds inmodels of cognitive function. For example, the selective 5-HT₆ receptorantagonist SB-271046 improved performance in the Morris water maze(Rogers, D. et al. Br. J. Pharamcol. 1999, 127 (suppl.): 22P). Theseresults were consistent with the finding that chronic i.c.v.administration of anti-sense oligonucleotides directed toward the 5-HT₆receptor sequence led to improvements in some measures of performance inthe Morris water maze (Bentley, J. et al. Br. J. Pharmacol. 1999, 126,7, 1537-42). SB-271046 treatment also led to improvements in the spatialalternation operant behavior test in aged rats.

Currently, several 5-HT₆ receptor antagonists are in clinicaldevelopment as potential treatments for cognitive dysfunction disorders.A first report that a 5-HT₆ receptor antagonist, SB-742457, is ofclinical benefit in Alzheimer's patients provides further evidence ofthe therapeutic potential of this approach.

N-(2-(6-fluoro-1H-indol-3-yl)ethyl-(2,2,3,3-tetrafluoropropoxy)benzylamineis a potent and selective 5-HT₆ receptor antagonist which is currentlyin clinical development. Its chemical structure is depicted below as thecompound of Formula I.

The synthesis ofN-(2-(6-fluoro-1H-indol-3-yl)ethyl-(2,2,3,3-tetrafluoropropoxy)benzylamine,its use for the treatment of disorders such as cognitive dysfunctiondisorders, and pharmaceutical compositions comprising this substance aredisclosed in U.S. Pat. No. 7,157,488 (“the '488 patent”). The '488patent further describes the preparation of the correspondingmonohydrochloride salt.

Although the synthetic methods disclosed in the above-identifiedreference suffices to prepare small quantities of material, it suffersfrom a variety of safety issues, low yields or processes that are notamendable to large scale synthesis. Thus, an unmet need exists toidentify processes for the manufacture of the compound of Formula I.

Accordingly, the present invention describes an efficient and economicalprocess for the preparation of the compound of Formula I that is usefulfor the production of kilogram quantities of material for preclinical,clinical and commercial use. In particular, the inventors haveunexpectedly discovered the role of ammonia to prevent dimerization inconnection with the reduction of the nitrile containing intermediate tothe corresponding amine.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation ofN-(2-(6-fluoro-1H-indol-3-yl)ethyl-(2,2,3,3-tetrafluoropropoxy)benzylamine,and pharmaceutically acceptable salts thereof, comprising the steps of

-   (a) reacting 6-Fluoroindole with an iminium ion species generated    in-situ from formaldehyde and dimethylamine in the presence of an    acidic aqueous solution to produce the compound of Formula II

-   (b) reacting the compound of Formula II with KCN in the presence of    DMF/water to produce the compound of Formula III;

-   (c) hydrogenating the compound of Formula III with H₂ in the    presence of NH₃ using a transition metal catalyst to produce the    compound of Formula IV;

and

-   (d) reacting the compound of Formula IV with    3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde in the presence of a    solvent followed by the addition of reducing agent.

A separate aspect relates to a process for the preparation of thecompound of formula II comprising the steps of:

-   -   (a) mixing a solution of diethoxymethane, water and formic acid;    -   (b) adding the solution of step (a) to a mixture of        6-fluoroindole, methylamine and acetic acid; and    -   (c) adding an aqueous basic solution.

In one embodiment, the solution of step (a) is mixed at a temperaturefrom about 75° C. to about 85° C.

In another embodiment, the solution of step (a) is stirred for less thanabout 2 hours.

In yet another embodiment, the solution of step (a) is added to amixture of 6-fluoroindole and acetic acid at a temperature from about2-8° C.

In another embodiment, the aqueous basic solution is NaOHaq.

In one embodiment, the yield is greater than 90%. In one embodiment, theyield is greater than 95%. In a separate embodiment, the yield isgreater than 98%.

Another aspect relates to a process for the preparation of the compoundof formula IV comprising the steps of:

-   -   (a) mixing (6-fluoro-1H-indol-3-yl)acetonitrile, 25% NH₃ in        water and a transition metal catalyst in an alcoholic solvent;        and    -   (b) hydrogenating the mixture with H₂.

In one embodiment, the transition metal catalyst is RaNi.

In another embodiment, the alcoholic solvent is methanol.

In yet another embodiment, the hydrogenation is run at a pressure ofabout 2.5 bars for about 16 hours.

In one embodiment, the hydrogenation is run at a temperature from about55° C. to about 65T.

Yet another aspect of the invention relates to a process for thepurification of 2-(6-fluoro-1H-indol-3-yl)-ethylamine comprising thesteps of:

-   -   (a) dissolving 2-(6-Fluoro-1H-indol-3-yl)-ethylamine in an        alcoholic solvent;    -   (b) adding a solution of L(+)-tartaric acid; and    -   (c) capturing the tartaric acid salt as a precipitate.

In one embodiment, the alcoholic solvent is methanol.

In one embodiment, ethyl acetate is used with the alcoholic solvent.

DETAILED DESCRIPTION

As previously indicated, the present invention is based on the discoveryof a feasible process that can obtainN-(2-(6-fluoro-1H-indol-3-yl)ethyl-(2,2,3,3-tetrafluoropropoxy)benzylamine,and pharmaceutically acceptable salts thereof, in an efficient andeconomical manner. The invention is explained in greater detail belowbut this description is not intended to be a detailed catalog of all thedifferent ways in which the invention may be implemented, or all thefeatures that may be added to the instant invention.

Accordingly, the invention was achieved by the development of the novelprocess described in Scheme I.

The process starting from commercially available 6-Fluoroindole can becharacterized as follows:

-   -   In the first step, commercially available 6-fluoroindole is        converted to (6-fluoro-1H-indol-3-ylmethyl)-dimethylamine. This        transformation involves a mannich reaction which generates an        iminium ion species in-situ. In one embodiment, the iminium ion        species is generated in-situ from diethoxymethane and        dimethylamine. In another embodiment, the iminium ion species is        generated in-situ from formaldehyde and dimethylamine. In        another embodiment, the reaction is run in an aqueous solvent.    -   In the second step, (6-fluoro-1H-indol-3-ylmethyl)-dimethylamine        is converted to (6-fluoro-1H-indol-3-yl)acetonitrile by reaction        with potassium cyanide in the presence of DMF/water at elevated        temperature. In another embodiment, the elevated temperature is        about the reflux temperature of the reaction mixture.    -   In the third step, (6-fluoro-1H-indol-3-yl)acetonitrile is        converted to 2-(6-fluoro-1H-indol-3-yl)-ethylamine. This        transformation involves the reduction of the nitrile to the        primary amine using hydrogen and a transition metal catalyst the        presence of ammonia. In another embodiment, the transition metal        catalyst is Raney Ni.    -   In the fourth step, 2-(6-Fluoro-1H-indol-3-yl)-ethylamine is        converted to        N-(2-(6-fluoro-1H-indol-3-yl)ethyl-(2,2,3,3-tetrafluoropropoxy)benzylamine        by coupling the amine with        3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde in the presence of a        solvent followed by the reduction of the imine bond with a        reducing agent. This transformation is a reductive amination        reaction. In one embodiment, the reducing agent is sodium        borohydride.

A considerable advantage of the process according to the inventionconsists in the fact that the use of ammonia in the third stepunexpectedly prevents the undesired dimerization of(6-fluoro-1H-indol-3-yl)acetonitrile while allowing the reaction toproceed smoothly and in high yield. Although the hydrogenation of basicnitriles with Raney Nickel has been known for some time (Huber, W. JACS1944, 66, 876-879), the use of only Raney Nickel in the preparation ofthe compound of formula I may not be practical.

The use of ammonia as a reaction additive to work in concert withcatalyst promoters such as Raney Nickel (Robinson and Snyder, OrganicSyntheses Collective Volume 3, 720-722) has been disclosed. However, theprior art points to the fact that the use of ammonia appears to decreaseoverall activity (Thomas-Pryor, et al. Chem. Ind. 1998, 17, 195,Viullemin, et al. Chem. Eng. Sci. 1994, 49, 4839-4849; and Fouilloux,New Frontiers in Catalysis—Proceedings of the 10^(th) InternationalCongress on Catalysis, 1992, Elsevier Science, Amsterdam, 255-2558). Foradditional examples, see EP 0913388, WO 00/27526, WO 99/22561, U.S. Pat.No. 5,777,166, and U.S. Pat. No. 5,801,286. Thus, the prior art appearsnot to teach nor suggest the use of ammonia in the reduction of nitrileswith Raney Nickel due to the decreased overall activity that isobserved.

To this end, the inventors have unexpectedly discovered that the use ofammonia in this process allows the reaction to proceed withoutdecreasing overall activity while preventing the formation of undesireddimerization.

The following are definitions for various abbreviations as used herein:

“DEM” is Diethoxymethane. “DMF” is N,N-Dimethylformamide. “MeOH” isMethanol. “THF” is Tetrahydrofuran. “6Fl” is 6-Fluoroindole.

“RaNi” is an activated Nickel Catalyst which is optionally doped with Feand Cr and that comes in different particle sizes. In one embodiment,the RaNi used is a sponge type metal catalyst commercially availablefrom Fluka. In another embodiment, the RaNi used is Johnson MattheyA5009 (5%, 33 microns) catalyst. In yet another embodiment, the RaNiused is Degussa's B111 W catalyst.“Cyanide source” is KCN, NaCN, and other agents which release the CN⁻anion.

“Aq” is Aqueous. “DI” is Distilled or Ultra Pure “RT” is RoomTemperature.

“eq” is Equivalence“g” is Grams.“ml” is Milliliter

“L” is Liter.

“kg” is Kilogram

“M” is Molar.

“w/w” is Weight per Weight

“HPLC” is High Performance Liquid Chromatography

The compound of Formula I forms pharmaceutically acceptable acidaddition salts with a wide variety of organic and inorganic acids andinclude the physiologically acceptable salts which are often used inpharmaceutical chemistry. Such salts are also part of this invention.Such salts include the pharmaceutically acceptable salts listed inJournal of Pharmaceutical Science, 66, 2-19 (1977) which are known tothe skilled artisan. Typical inorganic acids used to form such saltsinclude hydrochloric, hydrobromic, hydriodic, nitric, sulfuric,phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and thelike. Salts derived from organic acids, such as aliphatic mono anddicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoicand hydroxyalkandioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, may also be used. Such pharmaceutically acceptable saltsthus include chloride, bromide, iodide, nitrate, acetate, phenylacetate,trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,o-acetoxybenzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate,butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate,cinnamate, citrate, formate, fumarate, glycollate, heptarioate,hippurate, lactate, malate, maleate, hydroxymaleate, malonate,mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate,teraphthalate, propiolate, propionate, phenylpropionate, salicylate,sebacate, succinate, suberate, benzenesulfonate,p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate,2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, p-toluenesulfonate,xylenesulfonate, tartrate, and the like.

EXPERIMENTAL SECTION HPLC Description

The HPLC analysis was made under the following chromatographicconditions; column: Xterra RPI 8 (100 mm×4.6 mm, 3.5 μm), mobile phase:10 mM Ammonium carbonate (pH 8.5)/Acetonitrile, 86/14 to 14/86 (v/v, %),flow rate: 2 ml/min, column temperature: about 45° C., detection: UV at280 nm.

Example 1 Synthesis of the Compound of Formula II

Detailed syntheses of the compound of Formula II from commerciallyavailable 6-fluoroindole are provided below. Scheme II usesdiethoxymethane and dimethylamine to generate the “iminium ion species”.An alternative procedure using formaldehyde in place of diethoxymethaneis also provided below.

Synthetic Procedure:

Preparation of formaldehyde was carried out in reactor A. The synthesisof the compound of Formula II was carried out in reactor B.Precipitation of the final product was carried out in reactor C.

Procedure:

To reactor A were charged diethoxymethane (65 ml/54 g), water (50 ml)and formic acid (39 ml/47 g). The mixture was heated to about 80°C./reflux for about 2 hours and then cooled to about 20° C. To reactor Bwere charged 6-fluoroindole (50 g) and 80% acetic acid (66 ml/70 g, 2.5eq. to 6-fluoroindole). The suspension was cooled to 2-5° C. 40%Dimethylamine (aq) (103 ml/92 g, 2.2 eq. to 6-fluoroindole) was addeddrop-wise to reactor B keeping the temperature below about 15° C. Thereaction mixture was stirred for about 20 minutes and at the same timethe temperature was adjusted to 2-4° C.

The mixture from reactor A (DEM, water, formic acid, formaldehyde andethanol at about 20° C.) was added drop-wise to reactor B while keepingthe temperature at 2-8° C. The reaction mixture was stirred foradditional 10 minutes at 2-8° C. The reaction mixture was slowly warmedto about 40° C. over a 1 hour period. The reaction mixture was stirredat about 40° C. for an additional 1 hour. The reaction mixture wascooled to about 20° C.

To reactor C was charged 3M NaOH (800 ml, 1.24 eq. to the aceticacid+the formic acid) and the solution was cooled to about 10° C. Thereaction mixture from reactor B was added drop-wise to the NaOH solutionin reactor C while keeping the temperature at 10-15° C. (pH>14). Thesuspension was stirred for 40 minutes at 5-20° C. (pH>14). The productwas collected by filtration and the filter-cake was washed twice withwater (2×250 ml). The product was dried at about 60° C. under vacuum for16 hours. Yield: 95%. Purity by HPLC (280 nm): 98 area %.

Procedure Using Formaldehyde in Place of Diethoxymethane:

To a 250 L reactor, under N₂ atmosphere, was charged with about 40%aqueous dimethylamine (35.68 kg, 1.0 eqv.) at about 17° C. The mixturewas cooled to about 4.5° C. and glacial acetic acid (43.4 kg, 2.5 eq.)was added dropwise over 140 min while maintaining the temperature usingbelow about 15° C. After stirring for 20 min at about 3° C., 37% aqueousformaldehyde (25.9 kg, 1.1 eq.) was slowly added over about 20 min whilekeeping the temperature between about 0° C. to about 10° C.6-Fluoroindole (39.2 kg) was added. The reaction was exothermic andreached a final temperature of about 40° C., which was then cooled downto about 20° C. The reaction solution was slowly added in a 650 Lreactor charged with aqueous 3M NaOH over a period of about 40 min. Thesuspension was stirred for about 40 min while keeping the temperaturebetween about 5 and 20° C. The product was filtered, rinsed with DIwater (120 kg) and dried at about 50° C. to afford the compound ofFormula II (45.4 kg). Yield: 85%.

Example 2 Synthesis of the Compound of Formula ill

A detailed synthesis of the compound of Formula III from the compound ofFormula II is provided below in Scheme III.

Step-Wise Procedure:

(6-Fluoro-1H-indol-3-ylmethyl)-dimethylamine (65 g), KCN (31 g), DMF(195 ml) and water (104 ml) were charged to the reactor. The reactionmixture was heated to about 100-105° C. (strong reflux) for about 5-8hours. The reaction mixture was cooled to 20-25° C. Water (780 ml) andtoluene (435 ml) were charged to the reactor and the mixture was stirredvigorously for >2 hours. The organic and aqueous layers were separated.The organic layer was washed with 5% NaHCO₃ (6×260 ml), 2M HCl (260 ml),5% NaHCO₃ (260 ml) and 5% NaCl (260 ml), respectively. The organic layerwas filtered and concentrated to dryness. MeOH (260 ml) was added andthe solution was concentrated to dryness. The compound of Formula IIIwas isolated as a brown oil. Yield: 90%. Purity by HPLC (280 nm): 95%.MS m/z: 193 (M+H)⁺.

Example 3 Synthesis of the Compound of Formula IV

A detailed synthesis of the compound of Formula IV is provided below inScheme IV.

Synthetic Procedure:

The reduction of the compound of Formula III to Formula IV with hydrogenwas performed in an autoclave. Reactors A and reactor B were used toprepare the RaNi suspension and the reagent solutions which weretransferred to the autoclave. Reactors C and I) were used during work upand reactors E and F for the isolation of the compound of Formula IV asthe tartrate salt.

Procedure:

To reactor A were charged RaNi (66 g, water-wet) and MeOH (600 ml). 25%NH₃ in H₂O (375 ml) was charged (by vacuum line) to the autoclave. Thesuspension of RaNi in MeOH from reactor A was transferred (by vacuumline) to the autoclave. 25% NH₃ in H₂O (200 ml) was charged to reactor Aand then transferred (by vacuum line) to the autoclave. The compound ofFormula III (211 g) and MeOH (500 ml) are charged to reactor B and thentransferred (by vacuum line) to the autoclave. MeOH (600 ml) was chargedto reactor B and then transferred (by vacuum line) to the autoclave. 25%NH₃ in H₂O (175 ml) was charged to reactor B and then transferred (byvacuum line) to the autoclave. The reaction mixture was ventilated withnitrogen (3×N₂ at about P 2-3 bars). The reaction mixture was ventilatedwith hydrogen (4×H₂ at P 2 bar). The hydrogen pressure was adjusted toabout P 2 bar. The reaction mixture was heated to 60° C. The hydrogenpressure was adjusted to about P 2.5 bars. After about 16 hours at about60° C. and P(H₂) 2.5 bars the reaction mixture is cooled to roomtemperature. The reaction mixture was ventilated with nitrogen (3×N₂ atP 2.0-3.0 bar).

The reaction mixture was transferred from the autoclave to reactor C.The autoclave was washed with MeOH (500 ml). The methanol wastransferred to reactor C. The mixture was left without stirring for 2-16hours. The supernatant was collected in reactor D. MeOH (350 ml) wascharged to reactor D. The mixture was stirred slowly for 5 minutes andthen left without stirring for 2-16 hours. The supernatant was collectedin reactor D. The RaNi remains were collected for waste afterdestruction. Under a nitrogen atmosphere the supernatant in reactor Dwas filtered through celite. Additional MeOH (350 ml) was filteredthrough the celite to give a combined filtrate.

The filtrate was transferred to reactor E and concentrated under reducedpressure to approximately 2 volumes (˜400-450 ml). MeOH (600 ml) wascharged. The mixture was concentrated under reduced pressure toapproximately 2 volumes (˜400-450 ml). MeOH (600 ml) is charged. Themixture is concentrated under reduced pressure to approximately 2volumes (˜400-450 ml). MeOH (600 ml) was charged. The mixture wasconcentrated under reduced pressure to approximately 2 volumes (˜400-450ml). MeOH (1420 ml), ethyl acetate (1135 ml) and water (190 ml) werecharged. The solution in reactor E was heated to reflux.

In reactor F were charged L(+) tartaric acid (163.6 g) and MeOH (1135ml). The solution from reactor F was transferred to the solution inreactor E over 5-10 minutes, which results in precipitation of thedesired product as the tartrate salt. The mixture was stirred for about15 minutes at reflux and then cooled over 1 hour at 5-10° C. The mixturewas stirred for about 1 hour at 5-10° C. The product was collected byfiltration. The filter-cake was washed with cold ethyl acetate:MeOH(1:2, 380:760 ml). The white product was dried under vacuum at about40-45° C. for 16 hours. Yield: 82%. Purity by HPLC (280 nm): 99-100 area%. MS m/z: 179 (M+H)⁺.

Procedure Using BH₃-THF:

Alternatively, a BH₃-THF complex in place of the hydrogenation was alsoexplored to reduce the nitrile of the compound of Formula III to thecorresponding amine. A 1600 L reactor, under N₂ atmosphere, was chargedat RT with a toluenic solution containing the compound of Formula III(18.46 kg). A 1M solution of borane-THF complex (211 kg, 2.2 eqv.) wasslowly added to this solution over about 133 minutes while keeping thetemperature between 15 and 25° C. The resulting yellowish solution washeated to about 65° C. and stirred at this temperature for about 1 hour.After cooling down to about 21° C., the reaction mixture was addeddropwise over about 80 minutes to a well-stirred a 15% NaOH aqueoussolution under N₂ flow. The biphasic mixture was slowly heated to about50° C., stirred between about 50-60° C., heated to about 65° C. andstirred at this temperature for 1 hour.

After cooling down to about 25° C., the alkaline aqueous layer wasdecanted off for waste. The reaction mixture was then heated to about50° C. in order to distill the THF under reduced pressure (about 0.2barG). Dichloromethane (93 L) was added to the remaining aqueous phaseand aqueous HCl (18.8 kg aqueous HCl 37% and 22 kg DI water) was slowlyadded over about 30 minutes at about 22° C. The reaction mixture wasthen left to stir at RT for about 2 hours before being filtered, washedtwice with dichloromethane (2×19 L) and dried overnight under reducedpressure to afford the compound of Formula IV as the monohydrochloridesalt. Yield: 72% as 17.3 kg.

Example 4 Synthesis of the Compound of Formula I

The detailed synthesis ofN-(2-(6-fluoro-1H-indol-3-yl)ethyl-(2,2,3,3-tetrafluoropropoxy)benzylamineas the monohydrochloride salt is provided in Scheme V.

Procedure:

The tartrate salt of 2-(6-Fluoro-1H-indol-3-yl)-ethylamine (49.3 g) wasstirred in a mixture of toluene (270 ml), THF (100 ml), 2M NaOH (200 ml)and 15% NaCl (65 ml). The phases were separated. The organic phase waswashed with 5% NaCl (200 ml). The organic phase was concentrated underreduced pressure to dryness and the residue dissolved in isopropanol(400 ml).

3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (39 g) and isopropanol (200ml) were charged to the reaction mixture. The reaction mixture washeated at 60° C. for 2.5 hours and then cooled to about 55° C. To thehot reaction mixture was charged a suspension of NaBH₄ (7.4 g) inisopropanol (100+50 ml). The reaction mixture was heated at 55° C. for2.5 hours and then cooled to about 15-20° C. 2M HO (80 ml) was addeddrop-wise over a period of about 30 minutes. 2M HCl (140 ml) was addedover a period of 15 minutes. The mixture was stirred vigorously for 15minutes. The mixture was concentrated to half volume followed byaddition of 6M NaOH (83 ml) to pH≧14. Toluene (400 ml) was added. Thephases were separated and the organic phase was washed with 2M NaOH (200ml), 3% NH₄Cl (200 ml) and water (200 ml), respectively. The organicphase was filtered and concentrated to dryness. The residue wasdissolved in toluene (550 ml) and acetonitrile (50 ml). 6M HCl (33 ml)was added drop-wise. The resulting suspension was stirred for 2-4 hoursand then filtered. The filter-cake was washed with toluene/acetonitrile(9:1, 2×75 ml) and 0.1M HCl (2×75 ml), respectively. The crude HCl saltof the compound of Formula I was dried under vacuum at about 45° C. forabout 16 hours.

Final purification of HCl salt of the compound of Formula I HCl wasperformed by first dissolving the isolated HCl salt in acetone (300 ml).The solution was filtered and concentrated to a volume of about 90-120ml. Filtered 0.1M HCl (1900 ml) was added drop-wise over 30 minutes. Theresulting suspension was stirred at 20-25° C. for 16 hours and thenfiltered. The filter-cake was washed with filtered 0.1M HCl (200 ml) andfiltered water (150 ml), respectively. The purified HCl salt was driedat 40° C. under vacuum for about 16 hours and isolated as a white solid.Yield: 80%. Purity by HPLC (280 nm): >99.5%. MS m/z: 399 (M+H)⁺.

1-16. (canceled)
 17. A process for preparing a compound of formula I or a salt thereof,

the process comprising the steps of: (a) reacting a compound of Formula (IV)

with 3-(2,2,3,3-tetrafluoropropoxyl)-benzaldehyde in the presence of a solvent to form an imine-containing compound; and (b) reducing the imine-containing compound by using a reducing agent to form the compound of Formula I.
 18. The process of claim 17, wherein the solvent is isopropanol.
 19. The process of claim 17, wherein step (a) is performed at 60° C.
 20. The process of claim 17, wherein the reducing agent is sodium borohydride.
 21. The process of claim 17, wherein step (b) is performed at 55° C.
 22. The process of claim 17, wherein the process forms a salt of the compound of Formula I.
 23. The process of claim 17, wherein the salt of the compound of Formula I is a chloride, bromide, iodide, nitrate, sulfate, phosphate, hypophosphate, metaphosphate, pyrophosphate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptarioate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, p-toluenesulfonate, xylenesulfonate, or tartrate salt.
 24. The process of claim 23, wherein the salt of the compound of Formula (I) is a chloride salt.
 25. The process of claim 24, wherein the process further comprising reacting the compound of Formula I with hydrochloric acid to form the chloride salt.
 26. The process of claim 17, further comprising hydrogenating a compound of Formula III

With H₂ in the presence of NH₃ and a transition metal catalyst to form the compound of Formula IV.
 27. The process of claim 26, wherein hydrogenating the compound of Formula III comprises mixing the compound of Formula III, NH₃ in water, and the transition metal catalyst in an alcoholic solvent to form a mixture, and hydrogenating the mixture with H₂.
 28. The process of claim 27, wherein the transition metal catalyst is RaNi.
 29. The process of claim 27, wherein the alcoholic solvent is methanol.
 30. The process of claim 26, further comprising reacting a compound of Formula II

with KCN to produce the compound of Formula III.
 31. The process of claim 30, wherein reacting the compound of Formula II with KCN is performed in the presence of DMF and water.
 32. The process of claim 30, further comprising reacting 6-fluoroindole with formaldehyde and dimethylamine in the presence of an acidic aqueous solution to form a mixture.
 33. The process of claim 32, further comprising add the mixture to a basic aqueous solution to produce the compound of Formula II.
 34. The process of claim 32, wherein the formaldehyde is generated in situ from a solution of diethoxymethane, water, and formic acid.
 35. The process of claim 32, wherein the acidic aqueous solution comprises acetic acid.
 36. The process of claim 33, wherein the basic aqueous solution comprises sodium hydroxide. 